Cutting edge

May 26, 2000

Research to determine the layout of the molecular energy landscape may provide answers to key problems in the life sciences

It is a perennial problem; you stick your favourite poster to the wall only to find it lying on the floor the next day. Why does the tape decide not to stick any more? This change of strength as time progresses goes on at all levels of nature and is fundamental to many biological processes. A well-cited example is the leucocyte - white bloods cells that stick to the inside of blood capillaries. While they adhere to the vessel with enough strength to withstand being pulled off by the considerable hydrodynamic forces of the blood flowing over them, they roll along the vessel wall to a place of injury or infection.

This dynamic strength of adhesive bonds is a consequence of the change of energy as the two objects are pulled part, and the magnitude and rate of increase of this energy dictates how long the bond survives. Remarkably, it is now possible to measure the strength of individual molecular interactions as a function of time. These new biophysical techniques are beginning to explore the dynamic behaviour and social interaction of the molecular systems that underpin biological structure and function.

With the award of an Engineering and Physical Sciences Research Council advanced research fellowship, I am embarking on a programme of research to develop these tools to explore the energetics and dynamics behaviour of molecular systems. The ability to measure the change in energy with molecular conformation or interaction, termed the energy landscape, has wide-ranging implications across the life sciences. In particular, these landscapes dictate how a chain of amino acids folds into a functional protein and how a drug binds to a receptor target.

With the Human Genome Project we have several thousand times more protein sequences than solved structures and since it takes years to determine the structure of a new protein with current techniques, new methods are required to predict protein structure. The technique of dynamic force spectroscopy offers promise as a way to determine at least parts of the energy landscape.

There are problems with force spectroscopy, and it is these that I will investigate during this fellowship. The first is instrumental. The protein is unfolded or the drug removed from its receptor by attaching it to a spring and pulling. To reveal as much of the landscape as possible, a large range of interactions times, spanning many orders, have to be studied. To increase the time-span requires the combination of a range of techniques, and here I will investigate the use of the atomic force microscope, the biomembrane force probe and optical tweezers.

The second problem facing the science is in the interpretation of the data. Force spectros-copy measures certain features on a small part of the energy landscape. If one thinks of the landscape in geographical terms, these features are saddle points between hills. The behaviour of the system, however, also depends on the contour of the landscape between these passes. It is necessary, therefore, to fill in the gaps in data that are missing from the experimental studies using computational simulation.

The problem of the extended time periods with the experiment is minor compared with the time available for simulation. New methods are required to span the time disparity between computation and experiment.

Within this fellowship, I intend to develop dynamic force spectroscopy as a tool to determine the structure and function of molecules. This work sits at the interface between physics and biology, and I hope to answer problems in both these areas of science.

Phil Williams is a lecturer at the school of pharmaceutical sciences, University of Nottingham.

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